This research concerns three interrelated topics: (1) comparative studies on tRNAs and DNAs from normal and cancerous tissues; (2) studies on the effects of drugs on the modification of nucleic acids; and (3) the development of sensitive postlabeling methods for base composition and sequence analysis of RNA. Such studies are essential for defining the biochemical lesion(s) distinguishing cancer cells from normal cells and for the development of rational methods for the prevention and treatment of cancer. During the past year, our major emphasis has been on further defining the state of modification of tRNA and DNA in tumors, especially Morris hepatomas. Extensive differences were found when hepatoma nucleic acids were compared with their counterparts from normal liver. This entailed not only hypomethylation and hypomodification of hepatoma nucleic acids, but also primary sequence alterations of mitochondrial tRNA from a Morris hepatoma (5123D). In addition, we have continued studies of the effects on nucleic acid modifications of drugs known to affect DNA and/or RNA synthesis. Active compounds belonging to different classes, such as antimetabolites, stimulators, and inhibitors of cell division and compounds binding to DNA, have been investigated. Postlabeling methods developed over the past several years with support from this grant were applied extensively in these studies. We recently observed that interference with DNA methylation by drugs in vivo may lead to a long-term instability of m5C levels in DNA, an observation that may have implications for chemotherapy with 5-azacytidine and other inhibitors of nucleic acid methylation. (H)